title: Skeletal affinity of Tc(V)-DMS is bone cell mediated and pH dependent.
abstract: In spite of recent advances in bone cellular and molecular biology, there is still a poor correlation between these parameters and data obtained from bone scintigraphy. Diphosphonate derivatives radiolabelled with technetium-99m (Tc-BPs) have long been recognised as bone-seeking agents with an affinity for areas of active mineralisation. However, during clinical trials with a pH-sensitive tumour agent, the pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS] showed a noticeable osteotropic character only in bone pathologies (bone metastases, Paget's diseases) and lacked accumulation in normal mature bone. To decipher the osteotropic character of Tc(V)-DMS, a study at the cellular level was considered necessary. Moreover, to learn more about the role of Tc bone agents, acid-base regulation by bone tissue or cells was studied. First, biological parameters in body fluid were measured under systemic acidosis, induced by glucose administration, in normal and Ehrlich ascites tumour (EAT)-bearing mice. Then, in vivo biodistribution studies using Tc(V)-DMS or a conventional Tc-BP agent were carried out. The effect of glucose-mediated acidification on the skeletal distribution of the Tc agents in the mice provided valuable hints regarding the differential mediation of bone cells in skeletal tissue affinity for the agents. Thereafter, in vitro studies on osteoblast and osteoclast cells were performed and the comparative affinity of Tc(V)-DMS and Tc-BP was screened under diverse acidification conditions. Moreover, studies were also carried out on acid-base parameters related to the cellular uptake mechanism. Very specific pH-sensitive Tc(V)-DMS accumulation only in the osteoclastic system was detected, and use of Tc(V)-DMS in the differential detection of osteoblastic and osteoclastic metastases is discussed.
authors.affiliation: Development Bureau, Hamamatsu Photonics K.K., Hirakuchi 500, 434-8601, Hamakita City, Japan. shkazuko@hq.hpk.co.jp
authors.forename: Kazuko
authors.initials: K
authors.lastname: Horiuchi-Suzuki
authors.forename: Aya
authors.initials: A
authors.lastname: Konno
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ueda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Saori
authors.initials: S
authors.lastname: Nishio
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000138:Acidosis / Q000000981:diagnostic imaging / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002286:Carcinoma, Ehrlich Tumor / Q000000981:diagnostic imaging / Q000378:metabolism; D045744:Cell Line, Tumor; D006863:Hydrogen-Ion Concentration; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D009928:Organ Specificity; D010006:Osteoblasts / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D019783:Technetium Tc 99m Dimercaptosuccinic Acid / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D019275:Radiopharmaceuticals; D019783:Technetium Tc 99m Dimercaptosuccinic Acid