title: Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi.
abstract: OBJECTIVE
  The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with (99m)Tc-sestamibi.
  
  
  METHODS
  Doxorubicin-sensitive (143B-luc(+)) and resistant (MNNG/HOS-luc(+)) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a (99m)Tc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of (99m)Tc-sestamibi washout half-life (t (1/2)), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio.
  
  
  RESULTS
  A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t (1/2) of (99m)Tc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc(+) tumours (t (1/2) = 87.3 +/- 15.7 min) than in drug-sensitive 143B-luc(+) tumours (t (1/2) = 161.0 +/- 47.4 min) and decreased significantly with PSC833 (t (1/2) = 173.0 +/- 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc(+) tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc(+) tumours than in 143B-luc(+) tumours at early (1.55 +/- 0.22 vs 2.14 +/- 0.36) and delayed times (1.12 +/- 0.11 vs 1.62 +/- 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour.
  
  
  CONCLUSIONS
  The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of (99m)Tc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.
authors.affiliation: Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center, Leiden, The Netherlands. cgomes@ibili.uc.pt
authors.forename: Célia M F
authors.initials: CM
authors.lastname: Gomes
authors.forename: Mick
authors.initials: M
authors.lastname: Welling
authors.forename: Ivo
authors.initials: I
authors.lastname: Que
authors.forename: Niek V
authors.initials: NV
authors.lastname: Henriquez
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
authors.forename: Salvatore
authors.initials: S
authors.lastname: Romeo
authors.forename: Antero J
authors.initials: AJ
authors.lastname: Abrunhosa
authors.forename: M Filomena
authors.initials: MF
authors.lastname: Botelho
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Ernest K J
authors.initials: EK
authors.lastname: Pauwels
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Cleton-Jansen
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012516:Osteosarcoma / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi
chemical_list: D019275:Radiopharmaceuticals; D004317:Doxorubicin; D017256:Technetium Tc 99m Sestamibi